Publications (124) View all
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Article: PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer.
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ABSTRACT: It has recently been proposed that a three-gene model (SCMGENE) that measures ESR1, ERBB2, and AURKA identifies the major breast cancer intrinsic subtypes and provides robust discrimination for clinical use in a manner very similar to a 50-gene subtype predictor (PAM50). However, the clinical relevance of both predictors was not fully explored, which is needed given that a ~30 % discordance rate between these two predictors was observed. Using the same datasets and subtype calls provided by Haibe-Kains and colleagues, we compared the SCMGENE assignments and the research-based PAM50 assignments in terms of their ability to (1) predict patient outcome, (2) predict pathological complete response (pCR) after anthracycline/taxane-based chemotherapy, and (3) capture the main biological diversity displayed by all genes from a microarray. In terms of survival predictions, both assays provided independent prognostic information from each other and beyond the data provided by standard clinical-pathological variables; however, the amount of prognostic information was found to be significantly greater with the PAM50 assay than the SCMGENE assay. In terms of chemotherapy response, the PAM50 assay was the only assay to provide independent predictive information of pCR in multivariate models. Finally, compared to the SCMGENE predictor, the PAM50 assay explained a significantly greater amount of gene expression diversity as captured by the two main principal components of the breast cancer microarray data. Our results show that classification of the major and clinically relevant molecular subtypes of breast cancer are best captured using larger gene panels.Breast Cancer Research and Treatment 07/2012; 135(1):301-6. · 4.43 Impact Factor -
Article: Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.
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ABSTRACT: Background ER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only. Methods Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan-Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance. Results All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%-100%). Conclusions Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.Annals of Oncology 04/2012; 23(11):2866-73. · 6.43 Impact Factor -
Article: Enhanced mitochondrial complex gene function and reduced liver size may mediate improved feed efficiency of beef cattle during compensatory growth
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ABSTRACT: Growing ruminants under extended dietary restriction exhibit compensatory growth upon ad libitum feeding, which is associated with increased feed efficiency, lower basal energy requirements, and changes in circulating concentrations of metabolic hormones. To identify mechanisms contributing to these physiological changes, 8-month-old steers were fed either ad libitum (control; n = 6) or 60–70% of intake of control animals (feed-restricted; n = 6) for a period of 12weeks. All steers were fed ad libitum for the remaining 8weeks of experimentation (realimentation). Liver was biopsied at days −14, +1, and +14 relative to realimentation for gene expression analysis by microarray hybridization. During early realimentation, feed-restricted steers exhibited greater rates of gain and feed efficiency than controls and an increase in expression of genes functioning in cellular metabolism, cholesterol biosynthesis, oxidative phosphorylation, glycolysis, and gluconeogenesis. Gene expression changes during feed restriction were similar to those reported in mice, indicating similar effects of caloric restriction across species. Based on expression of genes involved in cell division and growth and upregulation of genes encoding mitochondrial complex proteins in early realimentation, it was concluded that reduced hepatic size and increased mitochondrial function may contribute to improved feed efficiency observed during compensatory growth. KeywordsCattle-Feed efficiency-Liver-MicroarrayFunctional and Integrative Genomics 04/2012; 10(1):39-51. · 2.84 Impact Factor -
Article: Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer.
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ABSTRACT: In breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously described micro-deletion event in the PTEN gene in the Basal-like SUM149 breast cancer cell line. We sought to identify if small regions of genomic DNA copy number changes exist by using a high density, gene-centric Comparative Genomic Hybridizations (CGH) array on cell lines and primary tumors. A custom tiling array for CGH (244,000 probes, 200 bp tiling resolution) was created to identify small regions of genomic change, which was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments were called micro-aberrations (<64 contiguous probes, ∼ 15 kb). Our data showed that primary tumor breast cancer genomes frequently contained many small-scale copy number gains and losses, termed micro-aberrations, most of which are undetectable using typical-density genome-wide aCGH arrays. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5' regions of the affected genes, including the promoter region, and high frequency of micro-aberrations was associated with poor survival. Using a high-probe-density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that can contribute to gene inactivation. These events may contribute to tumor formation through mechanisms not detected using conventional DNA copy number analyses.PLoS ONE 01/2012; 7(12):e51719. · 4.09 Impact Factor -
Article: Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival.
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ABSTRACT: Breast cancer is a heterogeneous disease with known expression-defined tumor subtypes. DNA copy number studies have suggested that tumors within gene expression subtypes share similar DNA Copy number aberrations (CNA) and that CNA can be used to further sub-divide expression classes. To gain further insights into the etiologies of the intrinsic subtypes, we classified tumors according to gene expression subtype and next identified subtype-associated CNA using a novel method called SWITCHdna, using a training set of 180 tumors and a validation set of 359 tumors. Fisher's exact tests, Chi-square approximations, and Wilcoxon rank-sum tests were performed to evaluate differences in CNA by subtype. To assess the functional significance of loss of a specific chromosomal region, individual genes were knocked down by shRNA and drug sensitivity, and DNA repair foci assays performed. Most tumor subtypes exhibited specific CNA. The Basal-like subtype was the most distinct with common losses of the regions containing RB1, BRCA1, INPP4B, and the greatest overall genomic instability. One Basal-like subtype-associated CNA was loss of 5q11-35, which contains at least three genes important for BRCA1-dependent DNA repair (RAD17, RAD50, and RAP80); these genes were predominantly lost as a pair, or all three simultaneously. Loss of two or three of these genes was associated with significantly increased genomic instability and poor patient survival. RNAi knockdown of RAD17, or RAD17/RAD50, in immortalized human mammary epithelial cell lines caused increased sensitivity to a PARP inhibitor and carboplatin, and inhibited BRCA1 foci formation in response to DNA damage. These data suggest a possible genetic cause for genomic instability in Basal-like breast cancers and a biological rationale for the use of DNA repair inhibitor related therapeutics in this breast cancer subtype.Breast Cancer Research and Treatment 11/2011; 133(3):865-80. · 4.43 Impact Factor
